Largazole (1) is a densely functionalized macrocyclic depsipeptide, recently isolated from the cyanobacterium Symploca sp. (Taori, K., et al. 2008 J. Am. Chem. Soc. 130:1806-1807 and 13506; Ying, Y., et al. 2008 J. Am. Chem. Soc. 130). This natural product exhibits exceptionally potent and selective biological activity, with two- to ten-fold differential growth inhibition in a number of transformed and non-transformed human- and murine-derived cell lines. The remarkable selectivity of this agent against cancer cells prompts particular interest in its mode of action and its value as a potential cancer chemotherapeutic.
It has previously been stated that “the 3-hydroxy-7-mercaptohept-4-enoic acid unit in 1 is unprecedented in natural products.” (Somech, R., et al. 2004 Cancer Treat. Rev. 30:461-472; Miller, T. A., et al. 2003 J. Med Chem. 46:5097-5116; Moradei, O., et al. 2005 Curr. Med. Chem.; Anti-Cancer Agents 5:529-560; Bolden, J. E., et al. 2006 Nat. Rev. Drug Discovery 5:769-784). In contrast to this assertion, the (S)-3-hydroxy-7-mercaptohept-4-enoic acid is, in fact, an essential motif in several cytotoxic natural products, including FK228 (FR901228) (Japanese Patent No. 03-141296, Jun. 17, 1991, Fujisawa Pharmaceutical Co., Ltd., Jpn. Kokai Tokkyo Koho J P, 1991; Ueda, H., et al. 1994; J. Antibiot. 47:301-310; Shigematsu, N., et al. 1994 J. Antibiot. 47:311-314; Ueda, H., et al. 1994 J. Antibiot. 47:315-323), FR901375 (Japanese Patent No. 03-141296, Jun. 17, 1991, Fujisawa Pharmaceutical Co., Ltd., Jpn. Kokai Tokkyo Koho J P; Ueda, H., et al. 1994; J. Antibiot. 47:301-310; Shigematsu, N., et al. 1994 J. Antibiot. 47:311-314; Ueda, H., et al. 1994 J. Antibiot. 47:315-323) and spiruchostatin (Masuoka, Y., et al. 2001 Tetrahedron Lett. 42:41-44) (structures depicted below), all of which are known histone deacetylase inhibitors (HDACi) (Townsend, P. A., et al. 2007 The bicyclic depsipeptide family of histone deacetylase inhibitors, in Chemical Biology; Schreiber, S. L., et al. Eds. Wiley-VCH Verlag GmbH & Co. 693-720).

The histone deacetylase enzymes are zinc metalloenzymes that catalyze the hydrolysis of acetylated lysine residues in chromatin and, thereby, regulate transcription in eukaryotic cells (Somech, R., et al. 2004 Cancer Treat. Rev. 30:461; Miller, T. A., et al. 2003 S. J. Med. Chem. 46:5097-5116; Moradei, O., et al. 2005 Curr. Med. Chem.; Anti-Cancer Agents 5:529-560; Bolden, J. E., et al. 2006 Nat. Rev. Drug Discovery 5:769-784). Their selective inhibition has recently become a major area of research in cancer chemotherapy (Minucci, S., et al. 2006 Nature Rev. Cancer 6:38-51). To date, eighteen HDACs have been identified, which are generally divided into four classes based on sequence homology to yeast counterparts (Taunton, J., et al. 1996 Science 272:408-411; Grozinger, C. M., et al. 1999 Proc. Nat. Acad. Sci. USA 96:4868-4873; Johnstone, R. W. 2002 Nature Rev. Drug Disc. 1:287-299). With respect to cancer therapy, there is an emerging consensus that Class I HDACs are clinically relevant, and that the undesirable toxicity associated with the first generation of HDAC inhibitors may be related to class indiscriminancy. As a result, programs have been initiated that are aimed at the synthesis and modification of peptide- and depsipeptide-based HDACi with the objective of optimizing structures for class- and even isoform-specific inhibition.